This paper will review data obtained primarily from our preclinical investigations that show that exposure to stress has a significant impact on drug taking. Stress increases reward associated with psychomotor stimulants, possibly through a process similar to sensitization, and a growing clinical literature indicates that there is also a link between substance abuse and stress in human addicts. One explanation for the high concordance between stress-related disorders and drug addiction is the self-medication hypothesis, which suggests that a dually-diagnosed person often uses the abused substance to cope with tension associated with life stressors or to relieve symptoms of anxiety and depression resulting from a traumatic event. However, another characteristic of drug self-administration is that drug delivery and its subsequent effects on the HPA axis are under the direct control of the individual. This controlled activation of the HPA axis may result in the production of an internal state of arousal or stimulation that is actually sought by the individual (i.e., the sensation-seeking hypothesis). During abstinence, however, exposure to stressors or drug-associated cues can stimulate the HP A axis to remind the individual about the effects of the abused substance, thus producing craving and promoting relapse. Stress reduction, either alone or in combination with pharmacotherapies targeting the HPA axis may prove beneficial in reducing cravings and promoting abstinence in individuals seeking treatment for addiction. Of primary importance is to reduce the impact of cocaine-associated environmental stimuli on the HPA axis so that they no longer function as triggers for relapse.

Lead and cadmium are potent environmental toxicants that affect populations living in Europe, Americas, and Asia. Identifying transporters for lead and cadmium could potentially 1 help us better understand possible risk factors. The iron transporter divalent metal transporter 1(DMT1) mediates intestinal transport of cadmium, and lead in yeast and fibroblasts overexpressing DMT1. In human intestinal cells knocking down expression of DMT1 attenuated uptake of cadmium and iron but not lead. A possible explanation is the expression of a second transporter for lead in intestine. In astrocytes, however, DMT1 appears to transport lead in an extracellular buffer at pH value. At neutral pH, transport was not mediated by DMT1 but rather by a transporter that is stimulated by bicarbonate and inhibited by 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid. The identity of this lead transporter is under study.

We have assessed amyloid ${\beta}-peptide$ $(A{\beta})-induced$ neurotoxicity in primary neurons and organotypic hippocampal slice cultures (OHC) in rat. Exposing cultured hippocampal and cerebellar granule neurons to $A{\beta}$ resulted in a decrease of MTT reduction, and in destruction of neuronal integrity. Treatment of these neurons with tunicamycin, an inhibitor of N-glycosylation in the endoplasmic reticulum (ER), also decreased MTT reduction in these neurons. S-allyl-L-cysteine (SAC), an active organosulfur compound in aged garlic extract, protected hippocampal but not cerebellar granule neurons against $A{\beta}$- or tunicamycin-induced toxicity. In the hippocampal neurons, protein expressions of casapse-12 and GRP 78 were significantly increased after $A{\beta}_{25-35}$ or tunicamycin treatment. The increase in the expression of caspase-12 was suppressed by simultaneously adding $1{\mu}M$ SAC in these neurons. In contrast, in the cerebellar granule neurons, the expression of caspase-12 was extremely lower than that in the hippocampal neurons, and an increase in the expression by $A{\beta}_{25-35}$ or tunicamycin was not detected. In OHC, ibotenic acid (IBO), a NMDA receptor agonist, induced concentration-dependent neuronal death. When $A{\beta}$ was combined with IBO, there was more intense cell death than with IBO alone. SAC protected neurons in the CA3 area and the dentate gyrus (DG) from the cell death induced by IBO in combination with $A{\beta}$, although there was no change in the CA1 area. Although protein expression of casapse-12 in the CA3 area and the DG was significantly increased after the simultaneous treatment of AI3 and IBO, no increase in the expression was observed in the CA1 area. These results suggest that SAC could protect against the neuronal cell death induced by the activation of caspase-12 in primary cultures and OHC. It is also suggested that multiple mechanisms may be involved in neuronal death induced by AI3 and AI3 in combination with IBO.